This Program Project Grant focuses on Integrative Neurobiology of Cardiovascular Regulation. Now in its 36th year, it represents the major scientific emphasis of the Cardiovascular Research Center at Iowa. The strength of this competitive renewal is based on the cohesion and synergy of its senior leadership, its constant evolution in concepts and approaches with new investigative talent, and the continuum of the effort from discovery of mechanisms to their translation into disease states in animal models and humans. The functional integration of the three components of autonomic control of the circulation is represented in four projects. Project I: Neural Processing of the Lamina Terminalis and Long-Term Regulation of Blood Pressure (Johnson, Hay) will identify molecular determinants of activation of central neurons in the lamina terminalis - a key regulatory site for the initiation of neurohumoral drive. Project II - Renin-Angiotensin-Aldosterone System and Sympathetic Activation in Obesity-Hypertension (Haynes, Mark, Rahmouni) will address the coupling of the two major components of neurohumoral drive to the cardiovascular system, namely the sympathetic nervous system and the renal-angiotensin-aldosterone system in as determinants of hypertension in obese humans. Project III - Cardiovascular Sensory Transduction by Acid Sensing Ion Channels (Abboud, Benson, Welsh) will address the molecular sensors involved in mechanotransduction of baroreceptors and chemoreceptor activation that maintain an autonomic balance of the cardiovascular system that is essential for survival in cardiovascular disease. Project IV - ROS Signaling in Baroreceptor and Sympathetic Neurons in Normal and Heart Failure States (Chapleau, Anderson, Weiss) will focus on ROS as a physiologic and pathologic modulator of afferent (baroreceptors) and efferent (sympathetic) neural activation, with fatal causal implications in a new model of heart failure. The molecular targets in the five projects also reflect a level of integration similar to the functional ones. There is convergence from the neurobiology of cardiovascular sensory organs (e.g. baro-chemo-receptors;circumventricular organs);to neurohumoral signaling molecules (angiotensin, aldosterone);to transmembrane receptors, reactive oxygen species, molecular transducters, and channels/channel protein. The Administration Core, the Vector Core and Animal Models Core are already providing invaluable service to the existing programs. The technical approaches are state-of-the-art, the animal models are well established, and the relevance to morbid conditions and fatal diseases such as heart failure, myocardial infarction, hypertension, atherosclerosis, dysautonomia, and obesity is direct. Common threads create the intellectual fabric of this program where the integrated outcome will be far greater than the sum of the components.